Polyacrylamide hydrogel as a soft tissue filler endoprosthesis

ABSTRACT

A hydrogel is obtained by combining acrylamide and methylene based-acrylamide, radical initiation and washing with pyrogen-free water or saline solution to give less than 3.5% by weight polyacrylamide, based on the total weight of the hydrogel. The hydrogel may be used as a soft tissue filler endoprosthesis. Also disclosed is a method of filling a soft tissue in a mammal using the endoprosthesis, and a prosthetic device comprising the polyacrylamide hydrogel.

FIELD OF INVENTION

[0001] The invention relates to a polyacrylamide hydrogel used as aprosthetic device for soft issue augmentation such as facial cosmeticsurgery, lip augmentation and soft tissue correction of the body. Thehydrogel comprises less than 3.5% polyacrylamide solid weight contentand pyrogen free water or saline solution.

BACKGROUND OF THE INVENTION

[0002] The success of plastic or reconstructive surgery depends to agreat extent on the physical properties of the materials utilised. Theymust most certainly be biocompatible, stable and non-toxic but they mustalso have physical properties that mimic the bodily tissue they arereplacing, as in reconstructive surgery, and mimic the bodily tissue inthe proximity of the endoprosthesis, as in cosmetic surgery.

[0003] Natural and synthetic polymers such as collagen, soya, glycerol,silicone, polyvinylpyrolidone and hyaluronic acid have been utilised asendoprostheses. Materials used for endoprostheses generally try toimitate the natural soft tissue and are intended to be safe to thehealth of the patient. Materials such as collagen are re-absorbed intothe body over short periods of time. Silicone and soya have encounteredserious safety issues. There is currently a need for a safe, stable,biocompatible material that possesses the physical properties to mimicsoft tissue.

[0004] Polyacrylamide gels have also been disclosed. WO 96/04943 relatesto a biocompatible hydrogel containing 3.5 to 6.0% cross-linkedpolyacrylamide. However, WO 96/04943 teaches that concentrations below3.5% make the hydrogel unstable.

[0005] GB 2114578 relates to a polyacrylamide gel for medical andbiological purposes containing 3 to 28% polyacrylamide with theremainder of the mass of the gel comprised of a physiological solution.According to GB 2114578, the prospective utility in the polyacrylamidegel lies in the manufacture of artificial crystalline lenses (contactlenses), a dense base in growing microorganisms. GB 2114578 disclosesthe preparation of gels having 4.0 to 20.0%, 5.0 to 18.0% and 6.0 to15.0% solid weight content.

[0006] U.S. Pat. No. 5,658,329 relates to an implantable endoprosthesiscomprising a shell filled with a polyacrylamide gel comprising 2 to 20%polyacrylamide by weight and a viscosity range of 15 to 75 Pas.

[0007] Formacryl® polyacrylamide is a soft-tissue endoprosthesisconsisting of 5% reticulated polyacrylamide polymer and 95% apyrogenicwater commercialised as an injectable device for medical and dental useto correct congenital or acquired deficits such as wrinkles, lines andscars. It is to be implanted with a syringe in the hypodermis.

[0008] U.S. Pat. No. 5,306,404 relates to a process for preparingpolyacrylamide gel plates for electrophoresis.

[0009] WO 99/10021 relates to an injectable, biocompatible hydrogelcomprising 0.5 to 10% polyacrylamide and an antibiotic or antiseptic. WO99/10021 is directed to the solving the problem of sappuration andrejection of the gel in its use an endoprosthesis.

SUMMARY OF THE INVENTION

[0010] In a first aspect, the invention relates to a hydrogel for use asa soft tissue filler endoprosthesis said hydrogel obtainable bycombining acrylamide and methylene bis-acrylamide, radical initiation;and washing with pyrogen-free water or saline solution so as to giveless than 3.5% by weight polyacrylamide, based on the total weight ofthe hydrogel.

[0011] In a second aspect, the invention relates to the use of ahydrogel comprising less than 3.5% by weight polyacrylamide, based onthe total weight of the hydrogel, for the preparation of anendoprosthesis for soft tissue filling. Similarly, the invention relatesto a method of filling soft tissue in a mammal comprising administeringan endoprosthesis wherein the endoprosthesis comprises a hydrogelcomprising less than 3.5% by weight polyacrylamide, based on the totalweight of the hydrogel.

[0012] A further object of the invention is to provide a prostheticdevice for soft tissue augmentation said device being injectable andcomprising a polyacrylamide hydrogel said hydrogel being obtainable bycombining acrylamide and methylene bis-acrylamide; radical initiation;and washing with pyrogen-free water or saline solution, so as to giveless than 3.5% by weight polyacrylamide, based on the total weight ofthe hydrogel;

GENERAL DESCRIPTION OF THE INVENTION

[0013] The term “facial” in intended mean of relation to all areas ofthe face, such as but not exclusively, the cheeks, the jaw, the neck,the forehead, under the eyes, the head area, and the nose.

[0014] The term “body contouring” is intended to mean cosmetic orreconstructive surgery wherein soft tissue is augmented in order tocorrect a cosmetic or non-cosmetic defect in the soft tissue in thebody, excluding the face, lips, breasts and penis. The present inventionrelates to facial corrections, lip augmentation, and body contouring.

[0015] The term hydrogel relates to the polyacrylamide polymer of theinvention comprising less than 3.5% polyacrylamide and at least 95%pyrogen-free water or saline solution whereas the term endoprosthesisrelates to the hydrogel present in the body.

[0016] The polyacrylamide hydrogel of the invention is obtainable by thepolymerisation of the monomers acrylamide andN,N′-methylene-bis-acrylamide under radical initiation, followed bywashing of the polymer with pyrogen-free water or saline solution. Thewashing of the polymer results in a swelling of the gel, due toabsorption of the pyrogen-free water or saline solution by the polymer.The swelling of the hydrogel influences the solid weight content of thegel, i.e. the amount of polymeric material, polyacrylamide. The solidweight content of the hydrogel influences, at least in part, thephysical (rheological) properties of the hydrogel and thus the abilityto mimic human tissue when used as an endoprosthesis.

[0017] The present investigators have prepared a hydrogel having thedesired rheological properties to act as a soft tissue fillerendoprosthesis which is completely atoxic, stable, and non-resorbable.The present investigators have developed the hydrogel to be particularlyamenable for use as an endoprosthesis for facial cosmetic orreconstructive surgery, for body contouring and for lip augmentation orreconstruction. The hydrogel of the present invention is not directedfor use as an endoprosthesis for breast or penis augmentation.

[0018] A first aspect of the invention relates to a hydrogel for use asa soft tissue filler endoprosthesis said hydrogel obtainable bycombining acrylamide and methylene bis-acrylamide in amounts so as togive less than 3.5% by weight polyacrylamide, based on the total weightof the hydrogel; radical initiation; and washing with pyrogen-free wateror saline solution. Typically, the hydrogel is obtained by saidcombining acrylamide and methylene bis-acrylamide in a molar ratio of150:1 to 1000:1. The hydrogel obtained in this manner has a structuralformula as shown in FIG. 1, is sterile, has transparent or colourlessappearance and has a pH in the range of 6.5 to 9.0, typically 7.0 to9.0. Furthermore the hydrogel of the invention is stable to oxygen, highpressure, high and low temperatures, enzymes and bacteria.

[0019] The invention thus relates to the use of a hydrogel comprisingless than 3.5% by weight polyacrylamide, based on the total weight ofthe hydrogel, for the preparation of an endoprosthesis for soft tissuefilling. Given the hydrogel of the invention is directed for use as anendoprosthesis, it must be stable. Furthermore, given the hydrogel ofthe invention is directed for use as an endoprosthesis for selectedparts of the human anatomy, the hydrogel typically comprises at least0.5% by weight polyacrylamide, based on the total weight of thehydrogel, preferably at least 1.0% by weight polyacrylamide, morepreferable at least 1.5% by weight polyacrylamide, such as at least 1.6%by weight polyacrylamide, based on the total weight of the hydrogel.Typically, the hydrogel of the present invention may have a solid weightcontent of 1.5, 1.6, 1.7 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6,2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, or 3.5% polyacrylamide, based onthe total weight of the hydrogel.

[0020] In a preferred embodiment of the present invention, the hydrogelcomprises about 1.9 to 2.9% by weight polyacrylamide, based on the totalweight of the hydrogel. The hydrogel typically further comprises atleast 95% by weight pyrogen-free water or saline solution, preferablypyrogen-free water. In a preferred embodiment, the hydrogel comprises atleast 96% by weight pyrogen-free water or saline solution, preferablypyrogen-free water, more preferably at least 97% by weight pyrogen-freewater or saline solution, preferably pyrogen-free water, such as 95%,95.5%, 96%, 96.5%, 97%, or 97.5% by weight pyrogen-free water or salinesolution, preferably pyrogen-free water.

[0021] A suitable saline solution has an osmolarity similar to that ofinterstitial fluid. Suitable saline solutions include but are notlimited to the group selected from 0.25-1% aqueous sodium chloride, aRinger-Lockart solution, an Earle solution, a Hanks solution, an Eaglemedium, a 0.25-1% glucose solution, a potassium chloride solution, and acalcium chloride solution. In a preferred embodiment, the salinesolution is an about 0.8-1% aqueous sodium chloride solution, such as a0.8, 0.9 or 1% aqueous sodium chloride solution.

[0022] Pyrogen-free water or saline solution is used for the washingprocess. The washing process serves, in part, to remove all but traceamounts of the monomers acrylamide and N,N′-methylene-bis-acrylamide.These monomers are toxic to the patient as well as detrimental to thestability of the hydrogel. The washing process is preferably such thatthe concentrations of the monomers acrylamide andN,N′-methylene-bis-acrylamide are below 50 ppm, more preferably below 40ppm, such as below 30 ppm, particularly preferably below 20 ppm,typically below 10 ppm, most preferably less than 5 ppm.

[0023] The solid weight content of the hydrogel of the present inventionis essentially completely contributed by the polyacrylamide andN,N′-methylene-bis-acrylamide with residual contribution by theinitiator. The hydrogel is substantially free of any other polymericcontent.

[0024] As stated, the hydrogel of the invention is biocompatible,atoxic, non-allergenic, non-resorbable, chemically inert and stable tooxygen, high pressure, high and low temperatures, enzymes and bacteria.In the event that the hydrogel is exposed to excessive amounts of UVlight, the physical features of the hydrogel are altered and isconverted into a glue-like substance. Advantageously, this substance isalso non-toxic.

[0025] Upon administration of the hydrogel, a thin layer of connectivetissue surrounds the endoprosthesis, enabling the endoprosthesis tobecome a stable part of the connective tissue. Due to the bio-stabilityof the hydrogel and the thin layer of connective tissue, theendoprosthesis may be easily removed from the patient when placed in thesubcutaneous area. This advantage is at least in part due to thestability of the hydrogel which in turn is at least in part due to thewashing process.

[0026] Several factors affect the rheological properties of thehydrogel, such as the relative amount of monomer used, the relativeamount of initiator, the temperature, the time of polymerisation, andother parameters of the polymerisation process, as well as the washingprocess. Thus, the polymerisation process may provide a hydrogel with anarray of viscosities having a solid weight content of less than 3.5%.The invention is directed to a hydrogel as a soft-tissue fillerendoprosthesis and thus the hydrogel preferably has a viscosity tailoredto the soft-tissue it is intended to mimic. The hydrogel of theinvention is typically for use as an injectable endoprosthesis forcosmetic or reconstructive surgery of the face, cosmetic orreconstructive surgery of the body (body contouring), and augmentationor reconstructive surgery of the lips.

[0027] The hydrogel of the invention may be injectable or implantableinto the subcutaneous layer of the epidermis, preferably the hydrogel isinjectable.

[0028] In one embodiment of the invention, the endoprosthesis is for usein facial cosmetic or reconstructive surgery and the hydrogel has acomplex viscosity of about 2 to 100 Pas, preferably about 5 to 90 Pas,such as about 5 to 60 Pas, such as about 10 to 60 Pas. Most preferably,the endoprosthesis for use in facial cosmetic or reconstructive surgerywas place by means of injection of the hydrogel.

[0029] Depending on the condition and region of the epidermis of theface where the soft-tissue filler is required (e.g. chin as opposed tocheek), the viscosity of the hydrogel may vary. Accordingly, thehydrogel may be for use in facial cosmetic or reconstructive surgery andhave a complex viscosity of about 2 to 20 Pas, preferably about 2 to 18Pas, such as about 2 to 15 Pas or 2 to 10 Pas, more preferably 2 to 7Pas, most preferably 3 to 5 Pas.

[0030] In typical embodiments, the endoprosthesis may be for uses incorrection of facial contour deformities due to ageing, acne, trauma,surgery, infection or congenital deformities. The facial featurestypically in need of correction are, for instance, the cheekbones,nasolabial folds, glabellar frowns, depressed contours of the mouth, thechin, the size or shape the lips, as well as other soft tissuedeficiencies of the face. The hydrogel restores the skin contourscorrecting soft tissue contour deformities of the face such as wrinklesand folds.

[0031] The hydrogel may serve for the preparation of an injectablehydrogel for lip enhancement or correct an array of aesthetic defectscaused by congenital, traumatic or ageing alterations.

[0032] As stated, invention relates to the use of the hydrogel for thepreparation of an endoprosthesis for the filling of soft tissue fillingselected from the soft tissue of the face and lips and soft tissue ofthe body. The hydrogel of the invention directed for use in the cosmeticor reconstructive surgery of the body (body contouring), preferably hasa complex viscosity of about 5 to 50 Pas, preferably about 7 to 40 Pas,most preferably about 7 to 30 Pas.

[0033] In the embodiment wherein the hydrogel is used in the preparationof an endoprosthesis for lip augmentation or lip reconstruction thehydrogel preferably has a complex viscosity of about 2 to 10 Pas, morepreferably 2 to 7 Pas, most preferably 3 to 5 Pas.

[0034] A further object of the invention is to provide a prostheticdevice for soft tissue augmentation said device being injectable andcomprising a polyacrylamide hydrogel said hydrogel being obtainable bycombining acrylamide and methylene bis-acrylamide in amounts so as togive less than 3.5% by weight polyacrylamide, based on the total weightof the hydrogel; radical initiation; and washing with pyrogen-free wateror saline solution.

[0035] The prosthetic device of the invention preferably comprises ahydrogel comprising at least 0.5% by weight polyacrylamide, based on thetotal weight of the hydrogel, preferably at least 1% by weightpolyacrylamide, more preferable at least 1.5% by weight polyacrylamide,such as at least 1.6% by weight polyacrylamide, based on the totalweight of the hydrogel. Typically, the hydrogel comprises about 1.9 to2.9% by weight polyacrylamide, based on the total weight of thehydrogel. The prosthetic device comprises the hydrogel which typicallycomprises at least 95% by weight pyrogen-free water or saline solution,preferably pyrogen-free water.

[0036] A further aspect of the invention relates to a method of fillingsoft tissue comprising administering an endoprosthesis wherein theendoprosthesis comprises a hydrogel comprising less than 3.5% by weightpolyacrylamide, based on the total weight of the hydrogel. The hydrogelmay be as described supra.

[0037] In an alternative embodiment of the invention, the prostheticdevice comprises cells, such as stem cells. Polyacrylamide provides anexcellent template and matrix for cell growth. Although the hydrogel ofthe invention allows, in itself, for a thin layer of connective tissuefrom the body of the patient to surround the device, the use of cells incombination with the hydrogel of the invention for the preparation ofthe device allows for cellular engraftment to the surrounding tissue.

[0038] The method of the invention typically comprises administering thehydrogel of the invention by injecting the hydrogel, into thesubcutaneous layer of the skin in the embodiments wherein theendoprosthesis is for facial cosmetic or reconstructive surgery or bodycontouring. In the embodiment wherein the endoprosthesis is for lipaugmentation or lip reconstruction, the injecting is above the muscletissue of the lip.

[0039] The method may comprise of more than one injection so as to coverthe desired area or to achieve the desired affect.

[0040] As stated, an alternative embodiment of the invention comprisesadministering the hydrogel of the invention in combination with cells,such as stem cells to allow for cellular engraftment of the prostheticdevice.

[0041] The gel to be injected is typically stored in a syringe suitablefor injecting the required amount for a single session treatment.Depending on the afflicted area, the amount of gel and thus volume ofthe syringe may vary, such as a syringe with a volume of 0.25-25 mL,such as a syringe selected from 0.5 mL, 0.7 mL, 1.0 ml, 1.5 mL. 2.0 mL,2.5 mL, 5.0 mL, 7.5 mL, 10 mL, 12.5 mL. 15 mL, 20 mL and 25 mL.Obviously, the prosthetic device for use in facial surgery or lipaugmentation be provided in a syringe in an array of volumes, typicallylower in volume than the volumes provided for by the prosthetic devicefor body contouring. For instance, the device for lip augmentation maybe provided in volumes of 0.5 ml or 0.7 mL or 1 mL whereas the devicefor body contouring may be provided in volumes of 2 mL, 5 mL, or 10 mL.These are purely illustrative examples and are not intended to limit thescope of the invention in any way—the device of the invention may beprovided in any volume required to perform the method.

[0042] As stated, the hydrogel is highly biocompatible. The method ofthe invention does not comprise of adding an antibiotic, analgesic oranti-inflammatory agent to the hydrogel.

[0043] In the preferred embodiment wherein the method comprises theinjection of the endoprosthesis, the injection comprises the use of asyringe with a thin gauge needle such as a 21-29 G needle. The necessaryamount of the gel is injected subcutaneously in a retrograde manner byinjecting the gel while withdrawing the needle. After the injection isperformed, a light manipulation may be required in order to obtain aneven distribution of the gel. Post-operative oedema may be treated withlocal packing of ice and mild pain and redness may be experienced duringthe first 2-3 days after injection.

[0044] In the embodiment wherein the method comprises injection of theendoprosthesis for lip augmentation or facial correction the needle ofthe syringe is typically particularly thin, such as a 25-29 G needle.For body contouring, the needle of the syringe may be in the range 21-23G.

EXAMPLES Example 1 Preparation of Hydrogel

[0045] The gel is a polyacrylamide gel manufactured by a polymerisationof the monomers of acrylamide and N,N′-methylene-bis-acrylamide. Thefinished product may have different viscosities.

[0046] The hydrogel has the empirical formula[C₃H₅NO]_(x)[C₇H₁₀N₂O₂]_(y) and the structural formula as shown in FIG.1

[0047] The hydrogel typically contains approximately 95% water. Theconcentration of the monomers acrylamide andN,N′-methylene-bis-acrylamide has been shown to be less than 10 ppm andis adequate for the desired stability of the final product, often lessthan 5 ppm.

[0048] The finished product must conform with respect to pH, absence ofheavy metals, refractive index, stability, absence of pyrogens, and mustbe sterile, practically inert, and be substantially free of monomers.

[0049] Preparation 1.1

[0050] The synthetic preparation suitably involves the followingoperations:

[0051] 1. Two mixtures, A1 and A2, are prepared. A1 comprises water,acrylamide, N,N′-methylene-bis-acrylamide,N,N,N′,N′-tetramethylene-ethylene-diamine (TEMED). A2 comprises waterand ammonium persulphate;

[0052] 2. The two mixtures are combined in the following ratio: 1990 mLof A1and 10 mL of A2 and kept at 45° C. and degassed with nitrogen for20 seconds;

[0053] 3. The reaction mixture is cast into several 100 mL beakers;

[0054] 4. Polymerisation is allowed to occur for 0.5 to 1.5 hours;

[0055] 5. The gel is demolded;

[0056] 6. Residual monomers are extracted and with equilibration in WFIwater for 92 hours, changing the water several times, typically 8 timesduring the 92 hours;

[0057] 7. The purified gels are homogenised by grinding with anvertically oscillating grid;

[0058] 8.The syringe is filled with the homogenised gel material;

[0059] 9. Autoclavation of the syringe

[0060] A typical method for preparing the hydrogel may be summarised as:

[0061] Preparation 1.2

[0062] Process summary: The gel is prepared by mixing an aqueous monomersolution of acrylamide and N,N′-methylene-bis-acrylamide as cross-linkerwith N,N,N′,N′-tetramethylene ethylene diamine (TMED) as co-initiatorand ammoniumpersulfate (APS) as free-radical initiator (redox-system).By degassing a bulk solution with nitrogen polymerisation starts. Afterfinal polymerisation the gel transferred into a washing tank with nettrays onto which the gel is placed. During water washing the gel swellsand monomer residues are extracted. The swollen gel is fed and evacuatedin a filling unit having the gel delivered in a syringe, which isautoclaved.

[0063] Two alternate formulations have been prepared, a lower- and ahigher- end viscosity formulation. Both formulations have a solid weightcontent of less than 3.5% and a complex viscosity in the range of 2 to50 Pa s, typically between 3 and 20 Pa s. TABLE 1 Chemical constituentlower end viscosity higher end viscosity acrylamide 502 g  547 g N,N′-methylene-bis- 2.2 g 4.6 g acrylamide TMED 3.0 g 2.6 g APS 5.4 g5.0 g Non-pyrogenic water Add 10 liter Add 10 liter

[0064] The above are typical preparations of the hydrogel and may beadjusted within certain ranges.

[0065] Preparation 1.3

[0066] Polyacrylamide formulations from inline cross-linking process

[0067] A particularly interesting method of preparing the hydrogels ofthe invention involves an inline cross-linking process. Two individualand eventually degassed flows, one being a pre-mix of acrylic amide,bis-methylene acryl amide (the cross-linker) and TEMED, the other beingthe AMPS initiator solution, are pumped into a static mixer for mixing,chemical initiation and subsequent extrusion downstream into a pipereactor made of Teflon or steel in which the polymerisation occurs.Washing of the gel is simplified due to high surface area of gel fromreactor.

[0068] By selecting monomer, cross-linker and initiator concentrationsand their relative molar ratios, and by regulating the two flow ratesand the polymerisation temperatures, it is possible to produce gels thatare varying in degree of crosslinking and in solids content.

[0069] Preparation 1.4

[0070] The reagents were combined in ratios described in Tables 2, 3 and4, and washed as described in the Tables (with pyrogen-free water unlessindicated otherwise) to give low, medium, and high viscosityformulations. Hydrogels with solid weight contents between 0.5 and 25%polyacrylamide were prepared. TABLE 2 Process parameters and features ofresulting gel: low viscosity formulations Iv1 Iv2 Iv3 Iv4 Iv5 Iv6Iv7^(d) Iv8^(e) Iv9 Iv10 Iv11 IV11 Iv12 washing time a) 19.5 73.75 9294.3 72.8 93.6 93.9 121 96.4 (hrs) dry matter^(i) 2.55 2.08 2.63 2.872.89 3.15 3.68 3.17 2.18 (5.10)^(f) (10.2)^(f) (10.1)^(f) (20.2)^(f) (%)2.36 2.58 2.67 2.82 2.90 3.57 3.52 2.09 molar ratio b) 976 700 488 3663239 488 488 701 701 488 488 488 AM:bisAM molar ratio 252 252 253 251252 249 252 252 252 252 252 504 2016 AM + BISAM:TEMED molar ratio 298299 298 298 298 299 298 298 298 298 298 596 2385 AM + BISAM:APS residualc) 89 5 2.97 2 5 1.4 0.97 0.97 monomer in ppm elasticity G′ 0.16 5.2314.3 26.6 57.05 71.7 39.2 28.5 28.5 11.1 (911)^(g) (1240)^(g) (9460)^(g)in Pa 20.1 viscosity .045 .88 2.35 4.37 9.1 11.5 6.29 4.55 4.55 1.8(145)^(g) (197)^(g) (1505)^(g) in Pa s 3.30 gelation time liquid highly12 2 2 2 2.5 2.5 3.17 0.00 1.21 3.5^(h) (min) viscous liquid

[0071] TABLE 3 Process parameters and features of resulting gel: mediumviscosity formulations mv1 mv2 mv3 mv4 mv5 washing time 97 211.5 96 94.890.3 (hrs) dry matter 3.14 2.49 3.25 3.29 3.22 (%) molar ratio 310 310290 289 289 AM:bisAM molar ratio 252 252 252 251 252 AM + BISAM:TEMEDmolar ratio 299 299 299 299 299 AM + BISAM:APS residual 1.6 1.5 monomerin ppm elasticity G′ 108.5 129 133.5 in Pa viscosity 17.4 20.6 21.30 inPa s gelation time 2.5 2.5 2.18 (min)

[0072] TABLE 4 Process parameters and features of resulting gel: highviscosity formulations hv1 hv2 hv3 hv4 hv5 washing time 119.5 516 12295.5 116.7 (hrs) dry matter 3.47 2.5 3.56 3.83 3.42 (%) molar ratio 260260 260 260 260 AM:bisAM molar ratio 315 315 604 313 314 AM +BISAM:TEMED molar ratio 376 376 755 375 376 AM + BISAM:APS residual 0.2monomer in ppm elasticity G′ 343 274 314.5 in Pa viscosity 54.7 43.6550.1 in Pa s gelation time 2.18 2.18 7.5 (min)

Example 2 Method of Administration

[0073] a) The injection of the gel may be performed under localanaesthesia, but for correction of wrinkles and folds, local anaesthesiais not necessarily required. For lip augmentation, anaesthesia throughthe nerve block is recommended.

[0074] b) The procedure must be performed under sterile conditions.Pharmaceuticals are not to be injected into the gel

[0075] c) The gel is pre-filled in sterile syringes of 1 mL withluer-lock and should be injected subcutaneously with a thin gaugeneedle, e.g 27 G. Needles should be CE-marked.

[0076] d) Inject the necessary amount of the gel subcutaneously in aretrograde manner by injecting the gel while withdrawing the needle. Apatient record label is part of the packaging and is removable and to beattached to the patient record to ensure that the product is traceable.

[0077] e) After the injection is performed, a light manipulation may beperformed in order to obtain an even or desired distribution of the gel.The injected gel will form a stable, soft part in the connective tissueand will give long lasting cosmetically satisfactory appearance.

[0078] f) Further injection sessions may be performed to achieve thedesired affect.

[0079] Post-operative procedures

[0080] If oedema occurs, ice packs may be applied locally. Exposure todirect sunlight or extreme cold or heat is advised until the initialswelling and redness has been resolved.

[0081] Adverse Events/Side Effects

[0082] It is not uncommon for patients to develop some pain within thefirst 2-3 days post-operatively. A mild degree of oedema will occur insome patients during the first 2-3 days after injection.

[0083] The correct injection technique is crucial for the final resultof the treatment and to be performed by authorised personnel.

[0084] The gel is sterilised (such as by moist heat or autoclavation).In the even that the package is damaged or opened but unused, sterilitymay be compromised and the contents should be discarded.Re-sterilisation is not advisable.

Example 3 Clinical Experience

[0085] 1) Approximately 900 patients underwent facial corrections withthe gel. The overall cosmetic results were excellent and the frequencyor adverse events was 0.02% (Kovanskaya V. A.; Scienctific conference,Oct. 13-16, 2000).

[0086] 2) A total of 150 adults undergoing correction of the contourdeformities of the face were treated with the injectable gel. The amountof gel injected was from 0.2 to 11 mL.

[0087] Scheduled visits took place at a screening day (3 days prior today 0), day 0 (first injection), day 7, day 28, month 3, month 6 and atend of study visit month 12 and underwent a physical examination andvital signs test, pregnancy test, blood and serum analysis, hematologytest, immunology test, urine analysis, concomitant treatment, sideeffect and events analysis, cosmetic outcome analysis by patient andsurgeon as well as completing a questionnaire according to the scheduleof Table 5.

[0088] Results

[0089] The overall rating of the outcome of the surgery was from verygood to good from both the patients and the surgeon. In some instances,the patients wanted to continue the treatment and receive furtherinjections. Several surgeons remarked spontaneously on the questionnairethat the patients were happy with the result and that the gel was easyto handle and administer.

[0090] The gel was very well tolerated. Only a few side-effects wererecorded and the Adverse Events oedema and inflammation were reported bythe patient. The Adverse Events resolved spontaneously after a few days.TABLE 5 Screening Day 0 (at (Facial least −3 correction) Day 7 ± Day 28± month 3 ± month 6 ± month 12 ± days) pre-op post-op 1 day 2 days 7days 7 days 7 days information/ X informed consent physical X X Xexamination vital signs X X X X X X pregnancy X test blood and samplingX X X serum analysis Haematology sampling X X X Immunology sampling X XX Urine analysis X X X Concomitant X X X X X X X treatment side effectsX X X X X X and events questionnaire X X X X X X (complaints) Cosmeticoutcome Patient X X X X Surgeon X X X X

1. A hydrogel for use as a soft tissue filler endoprosthesis saidhydrogel obtainable by combining acrylamide and methylenebis-acrylamide; radical initiation; and washing with pyrogen-free wateror saline solution, so as to give less than 3.5% by weightpolyacrylamide, based on the total weight of the hydrogel
 2. Thehydrogel according to claim 1, wherein said combining acrylamide andmethylene bis-acrylamide is in a molar ratio of 150:1 to 1000:1.
 3. Thehydrogel according to claim 1, wherein the hydrogel comprises at least0.5% by weight polyacrylamide, based on the total weight of thehydrogel, preferably at least 1% by weight polyacrylamide, morepreferable at least 1.5% by weight polyacrylamide, such as at least 1.6%by weight polyacrylamide, based on the total weight of the hydrogel. 4.The hydrogel according to claim 3 comprising about 1.9 to 2.9% by weightpolyacrylamide, based on the total weight of the hydrogel.
 5. Thehydrogel according to claim 1, wherein the hydrogel comprises at least95% by weight pyrogen-free water or saline solution, preferablypyrogen-free water.
 6. The hydrogel for according to claim 1 for use asan endoprosthesis for cosmetic or reconstructive surgery of the face,cosmetic or reconstructive surgery of the body (body contouring), andaugmentation or reconstructive surgery of the lips.
 7. The hydrogelaccording to claim 1, wherein the hydrogel is injectable or implantable,preferably injectable.
 8. The hydrogel according to claim 1 for use infacial cosmetic or reconstructive surgery said hydrogel having a complexviscosity of about 2 to 100 Pas, preferably about 5 to 90 Pas, such asabout 5 to 60 Pas, such as about 10 to 60 Pas.
 9. The hydrogel accordingto claim 7 for use in facial cosmetic or reconstructive surgery saidhydrogel having a complex viscosity of about 2 to 20 Pas, preferablyabout 2 to 18 Pas, such as about 2 to 15 Pas or 2 to 13 Pas, morepreferably 2 to 7 Pas, most preferably 3 to 5 Pas.
 10. The hydrogelaccording to claim 1 for use cosmetic or reconstructive surgery of thebody (body contouring), said biocompatible hydrogel having a complexviscosity of about 5 to 50 Pas, preferably about 7 to 40 Pas, mostpreferably about 7 to 30 Pas.
 11. The hydrogel according to claim 1 foruse in lip augmentation or lip reconstruction said biocompatiblehydrogel having a complex viscosity of about 2 to 10 Pas, morepreferably 2 to 7 Pas, most preferably 3 to 5 Pas.
 12. The hydrogelaccording to claim 1 for use in correction of facial contour deformitiesdue to ageing, acne, trauma, surgery, infection or congenitaldeformities.
 13. The hydrogel according to claim 12, wherein thecorrection is selected from the group consisting of corrections of thecheekbones, corrections of nasolabial folds, corrections of glabellarfrowns, corrections of depressed contours of the mouth, corrections tothe chin, corrections to size or shape the lips, and corrections toother soft tissue deficiencies of the face.
 14. A method of filling softtissue comprising administering an endoprosthesis wherein theendoprosthesis comprises a hydrogel comprising less than 3.5% by weightpolyacrylamide, based on the total weight of the hydrogel.
 15. Themethod according to claim 14, wherein the hydrogel comprises at least95% by weight pyrogen-free water or saline solution, preferablypyrogen-free water.
 16. The method according to claim 14, wherein theendoprosthesis does not comprise of an antibiotic, analagesic oranti-inflammatory agent.
 17. The method according to claim 14, whereinthe hydrogel is obtainable by combining acrylamide and methylenebis-acrylamide in a molar ratio of 150:1 to 1000:1.
 18. The methodaccording to claim 14, wherein the hydrogel comprises at least 0.5% byweight polyacrylamide, based on the total weight of the hydrogel, suchas at least 1% by weight polyacrylamide, preferably at least 1.5% byweight polyacrylamide, such as at least 1.6% by weight polyacrylamide.19. The method according to claim 14, wherein the hydrogel comprisesfrom about 2.0 to 3.0% by weight polyacrylamide, based on the totalweight of the hydrogel.
 20. The method according to claim 14, whereinthe soft tissue is sofit tissue of the face; and wherein theendoprosethesis is for facial cosmetic or reconstructive surgery; andwherein the hydrogel has a complex viscosity of about 2 to 20 Pas,preferably about 2 to 18 Pas, such as about 2 to 15 Pas or 2 to 10 Pas,more preferably 2 to 7 Pas, most preferably 3 to 5 Pas.
 21. The methodaccording to claim 14, wherein the soft tissue is soft tissue of thebody; and wherein the endoprosthesis is for cosmetic or reconstructivesurgery of the body (body contouring), and wherein the hydrogel has acomplex viscosity of about 5 to 50 Pas, preferably about 7 to 40 Pas,most preferably about 7 to 30 Pas.
 22. The method according to claim 14,wherein the soft tissue is soft tissue of the lip; and wherein theendoprosthesis is for lip augmentation or lip reconstruction; andwherein said hydrogel has a complex viscosity of about 2 to 10 Pas, morepreferably 2 to 7 Pas, most preferably 3 to 5 Pas.
 23. The methodaccording to claim 14, wherein the administering comprises injecting thehydrogel.
 24. The method according to claim 14, wherein theendoprosthesis is for facial cosmetic or reconstructive surgery or bodycontouring and the injecting is into the subcutaneous layer of the skin.25. The method according to claim 23, wherein the endoprosthesis is forlip augmentation or lip reconstruction and the injecting is above themuscle tissue of the lip.
 26. The method according to claim 23, furthercomprising administering cells, such as stem cells for cellularengraftment to the surrounding tissue.
 27. A prosthetic device for softtissue augmentation said device being injectable and comprising apolyacrylamide hydrogel said hydrogel being obtainable by combiningacrylamide and methylene bis-acrylamide; radical initiation; and washingwith pyrogen-free water or saline solution so as to give less than 3.5%by weight polyacrylamide, based on the total weight of the hydrogel. 28.The prosthetic device according to claim 27, wherein the hydrogelcomprises at least 0.5% by weight polyacrylamide, based on the totalweight of the hydrogel, preferably at least 1% by weight polyacrylamide,more preferable at least 1.5% by weight polyacrylamide, such as at least1.6% by weight polyacrylamide, based on the total weight of thehydrogel.
 29. The prosthetic device according to claim 28 comprisingabout 1.9 to 2.9% by weight polyacrylamide, based on the total weight ofthe hydrogel.
 30. The prosthetic device according claim 27, wherein thehydrogel comprises at least 95% by weight pyrogen-free water or salinesolution, preferably pyrogen-free water.
 31. The prosthetic deviceaccording to claim 27, further comprising cells, such as stem cells forcellular engraftment to the surrounding tissue.